Many human and mouse tumor cell lines secrete the cytokine CSF-1 (Colony Stimulating Factor-1, also known as Macrophage-Colony Stimulating Factor, M-CSF) that in turn attracts, promotes the survival, and activates monocyte/macrophage cells through the receptor c-fms (Feline McDonough Strain). Tumor associated macrophages (TAMs) (also known as tumor infiltrating macrophages (TIMs)) can be the major component of the tumor stroma comprising as much as 50% of the cell tumor mass. Kelly et al., 1988, Br. J. Cancer 57:174-177; Leek et al., 1994, J. Leukoc. Biol. 56:423-435. In surveys of primary human tumors, there is widespread evidence for CSF-1 mRNA expression. In addition, many studies have demonstrated that elevated serum CSF-1, the number of TAMs, or the presence of tissue CSF-1 and/or c-fms are associated with a poor prognosis for cancer patients.
TAMs support tumor growth, metastasis and survival by a variety of means, including direct mitogenic activity on tumor cells through secretion of PDGF, TGF-β and EGF and metastasis through production of ECM-degrading enzymes (reviewed in Leek and Harris, 2002, J. Mammary Gland Biol and Neoplasia 7:177-189 and Lewis and Pollard, 2006, Cancer Res 66:605-612). Another important means of tumor support by TAMs is the contribution to neo-vascularization of tumors via production of various proangiogenic factors such as COX-2, VEGFs, FGFs, EGF, nitric oxide, angiopoietins, and MMPs. Dranoff et al., 2004, Nat. Rev. Cancer 4:11-22; MacMicking et al., 1997, Annu. Rev. Immunol. 15:323-350; Mantovani et al., 1992, Immunol. Today 13:265-270. In addition, CSF-1-derived macrophages can be immunosuppressive via production of various factors such as prostaglandins, indolamine 2,3 dioxigenase, nitric oxide, IL-10, and TGFβ. MacMicking et al., 1997, Annu. Rev. Immunol. 15:323-350; Bronte et al, 2001, J. Immunother. 24:431-446.
CSF-1 is expressed both as a membrane-bound and as a soluble cytokine (Cerretti et al., 1988, Mol. Immunol. 25:761-770; Dobbin et al., 2005, Bioinformatics 21:2430-2437; Wong et al., 1987, Biochem. Pharmacol. 36:4325-4329) and regulates the survival, proliferation, chemotaxis and activation of macrophages and their precursors (Bourette et al., 2000, Growth Factors 17:155-166; Cecchini et al., 1994, Development 120:1357-1372; Hamilton, 1997, J. Leukoc. Biol. 62:145-155; Hume, 1985, Sci. Prog. 69:485-494; Sasmono and Hume, in: The innate immune response to infection (eds. Kaufmann, S., Gordon, S. & Medzhitov, R.) 71-94 (ASM Press, New York, 2004); Ross and Auger, in: The macrophage (eds. Burke, B. & Lewis, C.) (Oxford University Press, Oxford, 2002)).
The cognate receptor, which is the c-fms proto-oncogene (also known as M-CSFR, CSF-1R or CD115), is a 165-kD glycoprotein with an associated tyrosine kinase activity and belongs to the class III receptor tyrosine kinase family that includes PDGFR-α, PDGFR-β, VEGFR1, VEGFR2, VEGFR3, Flt3 and c-kit. Blume-Jensen and Hunter, 2001, Nature 411:355-365; Schlessinger and Ullrich, 1992, Neuron 9:383-391; Sherr et al., 1985 Cell 41:665-676; van der Geer et al., 1994, Annu. Rev. Cell. Biol. 10:251-337. The oncogenic form of c-fms, v-fms, which is carried by the McDonough strain of feline sarcoma virus is mutated to confer constitutively activated protein kinase activity (Sherr et al., 1985, Cell 41:665-676; Roussel and Sherr, 2003, Cell Cycle 2: 5-6). Expression of c-fms in normal cells is restricted to myelomonocytic cells (including monocytes, tissue macrophages, Kupffer cells, Langerhans cells, microglial cells and osteoclasts), hematopoietic precursors and trophoblasts. Arai et al., 1999, J. Exp. Med. 190:1741-1754; Dai et al., 2002, Blood 99:111-120; Pixley and Stanley, 2004, Trends Cell Biol. 14:628-638. Expression of c-fms has also been demonstrated in some tumor cells (Kirma et al., 2007, Cancer Res 67:1918-1926). A variety of in vitro studies and analyses of mutant mice demonstrate that CSF-1 is a ligand for c-fms(see, e.g., Bourette and Rohrschneider, 2000, Growth Factors 17:155-166; Wiktor-Jedrzejczak et al., 1990, Proc. Natl. Acad. Sci. U.S.A. 87:4828-4832; Yoshida et al., 1990, Nature 345:442-444; van Wesenbeeck and van Hul, 2005, Crit. Rev. Eukaryot. Gene Expr. 15:133-162). Binding of CSF-1 to c-fms induces autophosphorylation of the receptor at particular sites that result in downstream activation of signaling pathways including PI3-K/AKT and Ras/Raf/MEK/MAPK and macrophage differentiation is mediated primarily through persistent MEK activity (Gosse et al., 2005, Cellular Signaling 17:1352-1362). Very recent evidence indicates that interleukin-34 (IL-34) is also a ligand for c-fms (Lin, et al. 2008, Science 320:807-811).